Current treatments for human opioid abuse incorporate a variety of chronic pharmacotherapies, including methadone maintenance and newer therapies incorporating low efficacy opioid agonists (e.g., buprenorphine) or opioid antagonists (e.g., naltrexone). Preclinical studies of behavioral sequelae of such maintenance therapies may be useful in predicting behavioral and subjective effects of repeated opioid use in humans. The proposed projects will use drug discrimination assays and other behavioral assays as model systems to assess how pharmacological and behavioral factors modulate the development and expression of opioid tolerance and dependence during repeated treatment with clinically important opioid agonists. A primary goal during the upcoming period is to evaluate the hypothesis that abstinence precipitated by classical opioid antagonists in dependent organisms arises from inverse agonist actions, rather than from competitive antagonism, per se We will pay particular attention to the possibility that behavioral abstinence responses, as measured in free-operant, drug discrimination, and place conditioning assays, may represent uniquely sensitive indices of inverse agonist effects. Building on studies conducted during the previous award period, other experiments will evaluate whether the magnitude of dependence varies with the intrinsic efficacy of the agonist used to establish physical dependence Project 1 will define the doses, routes of administration, and pretreatment times over which compounds will function as antagonists of acute agonist actions of the classic agonists morphine and DAMGO. As controls for potential non-, or non-opioid, mechanisms in morphine dependence, key antagonists will be compared for their ability to alter effects of ? and opioid agonists and selected non-opioids. Project 2 will assess the ability of classical and putative neutral opioid antagonists to provoke abstinence in acutely and chronically dependent organisms, focusing on performance altering and discriminative stimulus effects. Project 3 will assess the ability of compounds to produce a functional up regulation of opioid receptors. In order to begin an initial characterization of the potential aversive actions of classical and putative neutral opioid antagonists, Project 4 will assess the ability of promising compounds to establish place aversions.